Project Summary/Abstract: Advances in cancer immunology has led to the successful use of patients' own immune cells to combat metastatic cancers. However, the therapeutic potential of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers is unclear. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of breast cancer development. Breast cancer is the most common internal cancer and second cause of cancer deaths among women in the United States. Importantly, the individuals at high risk of developing breast cancer due to underlying genetic mutations and those with premalignant lesions can be clinically identified and treated. Therefore, discovering an effective approach to activate the patients' own immune system against early breast precursor lesions may yield a lasting memory that can prevent breast cancer development and recurrence in this high-risk population. Our previous studies have demonstrated that a skin-derived immune factor called thymic stromal lymphopoietin (TSLP) suppresses the early stages of skin and breast cancer development. We have been able to extend these finding to clinics through a randomized double-blind clinical trial in which we find TSLP induction to promote a robust immune activation against skin cancer precursors and their complete clearance. In order to determine the precise mechanism of TSLP-induced immune response against early premalignant cells in the breast, and to extend our findings to other similar immune factors in high-risk patients, we aim to (1) determine the immune cells and signals that target breast premalignant cells in response to TSLP, (2) investigate the role of other immune factors released by breast cells that can induce immune response to block breast cancer development, and (3) determine the factors that are driving the immune response in the breast glands of patients with genetic mutations and utilize them for induction of an optimal immune response against early breast cancer. The outcomes of the proposed research will establish a foundation for the use of the immune system in blocking breast cancer development and provide novel therapeutic targets for breast cancer immunoprevention.